Intestinal infections with enterotoxin-producing pathogens, such as Vibrio cholerae, enteroxigenic Escherichia coli (ETEC), Shiga toxin-secreting E. coli (STEC), and Shigella dysenteriae, are major worldwide causes of diarrheal and not infrequently severe systemic disease. Treatment with conventional antibiotics is often ineffective, compromised by resistance, or contraindicated. The enterotoxins produced by these pathogens are central in disease pathogenesis, since mutation of the toxins or their host receptors markedly attenuates or abolishes disease. Because of their critical role, the respective host receptors constitute attractive targets for non-traditional antimicrobial strategies that do nt rely on conventional antibiotics, because the receptors, contrary to any bacterial factors, are constant and do not mutate over therapeutically relevant time frames, eliminating concerns about antibiotic resistance development. One major approach to leverage host receptor specificity is the development of pharmacological decoys that are identical to and compete with the receptors, and thus act as harmless sinks or sponges for the toxins until they are removed or destroyed by the host. This decoy strategy has been successfully tested in animal models using genetically- modified commensal bacteria as decoys, but a chemical drug candidate based on the same principle has not proven effective in a clinical trial of STEC infection. A key difference between these approaches is the receptor density of the decoys, with engineered bacteria displaying >1,000 greater surface receptor abundance and presumably better affinity than chemical agents. However, genetically altered, live microorganisms are problematic as therapeutics, as they are difficult to produce at pharmaceutical grade, hard to tailor, prone to mutate, and potentially colonize the host permanently and even cause disease. As an alternative, we propose to develop hybrid nanoparticles as decoys that display high density of toxin receptors on the surface, but are amenable to design modifications and can be readily produced under pharmaceutically desirable conditions. The project consists of two phases. In the milestone-driven exploratory R21 phase (Aim 1), we will develop a novel nanotechnology platform using cholera toxin as model toxin, and conduct in vitro and in vivo tests of nanoparticle activity. In the subsequent expanded development R33 phase (Aims 2 and 3), we will explore the capacity of nanoparticle decoys to protect against live V. cholerae in vitro and in vivo, and apply the nanoparticle strategy to other enterotoxins and their pathogens, ETEC, STEC, and S. dysenteriae. Together, the proposed project will develop a novel nanotechnology-based platform as a non-traditional antimicrobial strategy for the management of intestinal infections with enterotoxin-producing pathogens that cannot be treated with conventional antibiotics due to resistance or other biological reasons.